Significant progress was made during this reporting period. A large number of newly synthesized compounds were evaluated using in vitro assays. These results will be published in the next reporting period. A study in published in 2007 examined monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate agonist medications for cocaine dependence. This study reported that dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine. We contributed to the commentary related to methamphetamine and idiopathic pulmonary arterial hypertension and the role of the serotonin transporter. We also conducted experiments designed to determine if chronic fenfluramine (a SERT-substrate) administration increases plasma serotonin (5-hydroxytryptamine) to nontoxic levels. As noted in our publication: "Large elevations in blood serotonin (5-hydroxytryptamine;5-HT) can produce valvular heart disease in humans and laboratory animals. In accordance, one prevailing hypothesis (i.e., the 5-HT hypothesis) suggests that 5-HT transporter substrates like fenfluramine increase the risk for valvular heart disease by elevating plasma 5-HT, secondary to the release of 5-HT from platelets. The main purpose of this study was to determine whether chronic administration of fenfluramine increases plasma 5-HT to concentrations that are associated with the development of valvular heart disease. To the best of our knowledge, this is the first study to address this issue using an in vivo microdialysis method that measures plasma 5-HT in nonhypoxic rats. We examined the effects of chronic ( )-fenfluramine and fluoxetine on plasma levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in blood samples from conscious catheterized rats. Plasma indoles were measured by high-performance liquid chromatography with electrochemical detection in the dialysates of whole blood. The baseline plasma 5-HT level was 1.0 nM. Chronic fenfluramine (14-day minipump infusion) produced small increases in baseline plasma 5-HT ( 24-fold), whereas chronic fluoxetine had no effect. Chronic fenfluramine and fluoxetine markedly decreased whole-blood 5-HT and reduced the ability of acute fenfluramine to evoke 5-HT release. Elevations in baseline plasma 5-HT produced by chronic fenfluramine are far below the micromolar levels necessary to produce valvular heart disease. Furthermore, chronic fenfluramine reduces the ability of acute fenfluramine to increase plasma 5-HT, suggesting that the 5-HT hypothesis cannot explain the increased risk of valvular heart disease in patients treated with fenfluramine." These findings suggest that small elevations of plasma 5-HT produced by SERT substrates is unlikely to cause adverse effects.